There are 15,000 new cases of primary brain tumors with 11,000 deaths annually in the United States, and brain tumors are the second leading cause of cancer death in children and young adults. Even with aggressive surgical and radiation therapies, many patients with brain tumors have survival times of only 9 to 10 months. Hence, the prognosis for this disease is bleak and compels investigation of new therapeutic avenues. Direct introduction of the therapeutic genes into tumor cells may provide an effective treatment of brain tumors. One strategy is to confer drug sensitivity to tumor cells by inserting a recombinant gene from the Herpes Simplex virus that codes for the thymidine kinase (HSV-tk) enzyme. Thymidine kinase converts the anti-viral drug ganciclovir (GCV) into a form that is toxic to dividing cells. This approach is especially suitable for the treatment of brain tumors since the normal brain tissue is made largely of non-dividing cells. We have demonstrated in laboratory studies using animal models of experimental brain tumors that adenovirus-mediated transfer of the HSV-tk gene and GCV treatment resulted in eradication of the tumors and significant increases in life spans. This phase I study was designed to study the safety of gene therapy for patients with brain tumors. Patients with malignant brain tumors (Glioblastoma and Anaplastic Astrocytoma) who had received all standard therapy (surgery, radiotherapy, and in most cases, chemotherapy) and who had recurrent tumors were treated with intra-tumoral injections of replication-defective adenovirus vector delivering the Herpes Simplex Virus thymidine kinase gene. A single injection of 1 cc of a solution containing the vector was made into the center of the tumor. A dose escalation protocol was used, ranging from 1x108 i.u. to 1x1011 i.u. GCV was administered intravenously at 10mg/kg/day for 14 days. Each patient was carefully monitored for adverse effects. The primary objective of this study was to determine whether the treatment was associated with significant toxicity. The study of efficacy is planned in which the vector will be distributed more uniformly throughout the tumor followed by the GCV administration.